The subject-matter of the present invention is a process of use in converting the 4xe2x80x3 (S)-OH functional group of the cladinose unit of an azamacrolide to 4xe2x80x3 (R)xe2x80x94NH2.
The present invention relates more particularly to the field of macrolide antibiotics of erythromycin type and more particularly their azamacrolide derivatives which form the subject-matter of Patent EP 508,699 and which correspond to the following general formula: 
in which R is a hydrogen atom or a C1-C10 alkyl, C2-C10 alkenyl or C6-C12 arylsulphonyl group, which are, if appropriate, substituted.
These compounds are obtained from erythromycin and their synthesis involves two major stages:
the creation of the 8a-azalide macrocycle starting from the (Z) oxime, which is subjected to a stereospecific Beckmann rearrangement, and
the modification of the cladinose group at the 4xe2x80x3 position, which consists of the conversion of the 4xe2x80x3 (S)-OH to 4xe2x80x3 (R)-NH2, that is to say with inversion of configuration, which can be illustrated as follows: 
In fact, the route currently used to provide for this conversion of the 4xe2x80x3 (S)-OH to 4xe2x80x3 (R)-NH2 is not completely suitable for production on an industrial scale.
It involves, successively, an oxidation of the hydroxyl functional group at the 4xe2x80x3 position to a ketone functional group and then the conversion of this ketone to an oxime, which, by reduction, results in an approximately 1 to 1 mixture of the expected amino derivative and of its 4xe2x80x3 epimer.
This synthetic route consequently has the major disadvantage of requiring the formation of sp2 C-4xe2x80x3 intermediates and thus of losing the stereochemical information initially present at the sp3 C-4xe2x80x3 of the cladinose unit. This result is all the more of a nuisance since the isomers, acquired on conclusion of this synthetic route, are obtained with a low yield of about 20% and are in addition difficult to separate. Thus, for a crude reaction yield of about 20%, only approximately 7% of the amino derivative with inversion of configuration is obtained.
The object of the present invention is specifically to provide a new access route to these derivatives, aminated at the 4xe2x80x3 position, which advantageously makes it possible to retain a significant stereoselectivity and provides a satisfactory yield.
More specifically, a first subject-matter of hi the present invention is a process for the preparation of a compound of general formula I 
in which:
R is a hydrogen atom or a C1-C10 alkyl, C2-C10. alkenyl or C6-C12 arylsulphonyl group, which are, if appropriate, substituted, and
A, which are identical or different, are
a hydrogen atom,
a nitrogen atom, if appropriate substituted,
a C1-C4 alkyl group, which is optionally substituted by one or more aryl groups, which are, if appropriate, substituted,
an R2CO or R2SO2 group, with R2 being a hydrogen atom, a C1-C18 alkyl group or an aryl group, which are, if appropriate, substituted,
∇ means that the C in the 4xe2x80x3 position has undergone an inversion of configuration with respect to the formula II, from a compound of general formula II 
xe2x80x83with:
R as defined in general formula I and
P1 being a protective group for the hydroxyl functional group at the 2xe2x80x2 position, characterized in that it comprises at least the stages consisting in:
activating the hydroxyl functional group at the 4xe2x80x3 position in the compound of general formula II, in order to obtain a compound of general formula III 
xe2x80x83in which:
R and P1 are as defined in general formulae I and II and
OR1 is a leaving group,
bringing the said compound of general formula III thus obtained into contact with a nitrogenous nucleophilic derivative under conditions which are sufficient to allow the stereoselective displacement of the hydroxyl functional group activated by the said nitrogenous nucleophile, and
deprotecting the hydroxyl functional group at the 2xe2x80x2 position, in order to result in the expected compound of general formula I.
The claimed process thus has the significant advantage of not requiring the formation of the sp2 C-4xe2x80x3 intermediate necessarily generated in the prior synthetic route discussed above. It involves only an inversion of configuration at the 4xe2x80x3 position and this inversion is obtained efficiently by displacement by a nitrogenous nucleophile of the activated alcohol functional group present at this 4xe2x80x3 position.
Consequently, the claimed process proves to be particularly advantageous for preparing with a very satisfactory yield, a 4xe2x80x3 (R)-NA2 derivative of general formula Ixe2x80x2
with A and R as defined above from a 4xe2x80x3 (S)-OH azamacrolide derivative of general formula IIxe2x80x2
with R and P1 as defined above.
As regards the leaving group represented by OR1 in general formula III, it is preferably selected from C1 -C20 alkyl sulphonates, C5-C6 aryl or heteroaryl sulphonates or C6 to C26 alkylaryl sulphonates, which are substituted, if appropriate, by one or more halogen atoms, preferably fluorine, and/or a nitro, cyano or trifluoromethyl group.
The leaving group represented by OR1 in general formula III is preferably a group selected from mesylate, triflate and tosylate and is more preferably a triflate group.
Use may in particular be made according to the invention, as nitrogenous nucleophilic compound, of compounds of the following types: ammonia, amines which may or may not be substituted by deprotectable groups, such as a benzyl group or one of its derivatives, amides, imides, sulphonamides, sulphonimides, hydrazines or azides.
According to a preferred alternative form of the claimed process, it is more preferably an organic organosoluble azide which can be generated in situ.
The leaving groups deriving from the activation of the hydroxyl functional group at the 4xe2x80x3 position in the general formula II by a compound of formula IVA or IVB 
with:
X being a halogen atom or a nitrogenous heterocycle, preferably an imidazole ring, and
B being a C1-C20 alkyl, C5-C6 aryl or heteroaryl or C6-C26 alkylaryl group, which are or are not substituted by one or more halogen atoms, preferably fluorine, and/or a nitro, cyano or trifluoromethyl group, are very particularly suitable for the invention.
The compound of general formula III thus obtained is preferably brought into contact with an organosoluble azide in order to result, by stereoselective nucleophilic displacement, in a compound of general formula V 
in which R and P1 are as defined in general formula I and ∇ means that the C in the 4xe2x80x3 position has undergone an inversion of configuration with respect to the formula II,
The C-4xe2x80x3 carbon of the compound II preferably has a S configuration and the C-4xe2x80x3 carbon of the compound V a R configuration.
According to this alternative form of the claimed process, a reduction of the said compound of formula V can additionally be carried out, prior or otherwise to the deprotection of the hydroxyl functional group at the 2xe2x80x2 position, so as to obtain a compound of general formula I in which A is a hydrogen atom. This reduction of the azide functional group can be carried out by any conventional method, such as those described by E. F. V. Scriven et al., Chem. Rev. (1988), 88, 297-368. A catalytic reduction with hydrogen or hydrazine in the presence of palladium-on-charcoal, for example, or of Raney nickel can in particular be carried out.
On conclusion of this reduction, the expected 4xe2x80x3 (R)-NH2 amino derivative, that is to say with inversion of configuration, is thus recovered with a satisfactory yield.
Consequently, this alternative form of the claimed process is very particularly of use in the preparation of the compounds of general formula Ixe2x80x3
in which:
R is a hydrogen atom or a C1-C10 alkyl, C2-C10 alkenyl or C6-C12 arylsulphonyl group, which are, if appropriate, substituted, from a compound of general formula II as defined above.
Mention may very particularly be made, as illustration of the azides which are suitable for the present invention, of tetra(C1 to C20 alkyl)ammonium or -phosphonium azide, substituted or unsubstituted triarylsulphoniums and hexa(C1 to C20 alkyl)guanidiniums.
According to a preferred alternative form of the invention, it is a tetraalkylammonium azide and more particularly tetrabutyl- or tetraoctylammonium azide.
In a specific embodiment of the invention, the azide derivative is formed in a two-phase medium and more specifically in solid/liquid phase transfer. In this case, the organosoluble azide is generated in situ from an inorganic azide, such as sodium azide, and from a phase transfer agent in the presence of the compound of general formula III in an organic solvent. The phase transfer agent is preferably a tetra(C1 to C20 alkyl)ammonium or -phosphonium methanesulphonate.
As regards the compound of general formula II, it is generally obtained beforehand by protection of the hydroxyl functional group at the 2xe2x80x2 position in the corresponding derivative. Of course, this protection is carried out conventionally using a conventional protective group for the hydroxyl functional group, such as those which appear in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Second Edition, Theodora W. Greene and P. G. Wuts, Wiley Intersciences, p. 10-142. The procedures for carrying out the protecting and deprotecting operations are also described in the work referred to above.
Following this protection of the hydroxyl functional group at the 2xe2x80x2 position, the hydroxyl functional group at the 4xe2x80x3 position is activated. This activation of the compound of general formula II is also carried out under conventional operating conditions, such as those described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Second Edition, Theodora W. Greene and P. G. M. Wuts, Wiley Intersciences, p. 117-118. The examples submitted below describe a detailed procedure for the activation of the 4xe2x80x3 hydroxyl functional group with triflic anhydride.
As regards the nucleophilic substitution reaction, it is carried out in an organic solvent, preferably an anhydrous organic solvent. In the preferred alternative form of the invention employing an organosoluble azide, aromatic solvents, such as benzene and toluene, or ethers, such as THF or methyl tert-butyl ether, are suitable in particular as solvents.
The nitrogenous nucleophilic compound, preferably the azide, is used in a proportion of approximately 1 to 30 equivalents with respect to the compound of formula III and preferably in a proportion of approximately 1 to 5 equivalents.
The temperature is conventionally between xe2x88x9220 and 180xc2x0 C. As a general rule, it is adjusted so as to favour the kinetics of the reaction without harming the stability of the compounds.
According to a preferred alternative form of the invention, in the first stage, the hydroxyl functional group at the 4xe2x80x3 position is activated by a trifluoromethanesulphonate group and the nucleophilic substitution is carried out with inversion of configuration with tetrabutyl- or tetraoctylammonium azide in toluene at room temperature.
According to a preferred alternative form of the invention, R is a methyl group in the general formulae I, Ixe2x80x2, IIxe2x80x2, IIxe2x80x3, III and V and A a hydrogen atom in the general formula I and Ixe2x80x2.
Another subject-matter of the present invention is the compounds of general formula VI 
in which
P2 is a hydrogen atom or a protective group,
R is a hydrogen atom or a C1-C10 alkyl, C2-C10 alkenyl or C6-C12 arylsulphonyl group, which are, if appropriate, substituted, and
OR1 is a leaving group, as intermediates in the preparation of a compound of general formula I.
More preferably, R is a methyl group and OR1 is a triflate group and more preferably the C-4xe2x80x3 carbon has a R configuration.
The present invention also relates to the compounds of general formula VII 
in which
P2 is a hydrogen atom or a protective group,
R is a hydrogen atom or a C1-C10 alkyl, C2-C10 alkenyl or C6-C12 arylsulphonyl group, which are, if appropriate, substituted, and
A, which are identical or different, are
a nitrogen atom, if appropriate substituted,
a C1 -C4 alkyl group, which is optionally substituted by one or more aryl groups, which are, if appropriate, substituted,
as intermediates in the preparation of a compound of general formula I.
More preferably, R is a methyl group and NA2 an N3 group and more preferably, the C-4xe2x80x3 carbon has a R configuration.
The examples which appear below are presented by way of illustration and without implied limitation of the present invention.